ISSN 0100-879X
CLINICAL INVESTIGATION
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Volume 45 (7) 565-680 July 2012
Braz J Med Biol Res, July 2012, Volume 45(7) 652-655
doi:
10.1590/S0100-879X2012007500079
Evaluation of renal function in sickle cell disease patients in Brazil
G.B. Silva Junior, A.B. Libório, A.P.F. Vieira, A.X. Couto Bem, A.S. Lopes Filho, A.C. Figueiredo
Filho, A.L.M.O. Guedes, J.H. Souza, C.M.B.E. Costa, R. Costa and E.F. Daher
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Evaluation of renal function in sickle
cell disease patients in Brazil
G.B. Silva Junior
1,2, A.B. Libório
2, A.P.F. Vieira
1, A.X. Couto Bem
1, A.S. Lopes Filho
1,
A.C. Figueiredo Filho
1, A.L.M.O. Guedes
1, J.H. Souza
3, C.M.B.E. Costa
3,
R. Costa
4and E.F. Daher
11Programa de Pós-Graduação em Ciências Médicas, Departamento de Medicina Clínica, Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, CE, Brasil 2Faculdade de Medicina, Centro de Ciências da Saúde, Universidade de Fortaleza, Fortaleza, CE, Brasil 3Centro de Hematologia e Hemoterapia do Ceará, Fortaleza, CE, Brasil 4Hematology/Oncology Division, Allegheny General Hospital, Pittsburgh, PA, USA
Abstract
The objective of this study was to investigate renal function in a cohort of 98 patients with sickle cell disease (SCD) followed up at a tertiary hospital in Brazil. Clinical and laboratory characteristics at the time of the most recent medical examination were analyzed. Renal function was evaluated by the estimation of glomerular filtration rate (GFR) by the criteria of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). We compared patients with normal GFR to patients with decreased GFR (<60 mL·min-1·(1.73 m2)-1) and hyperfiltration (>120 mL·min-1·(1.73 m2)-1). Comparison between patients according to the use of
hydroxyurea and comparison of clinical and laboratory parameters according to GFR were also carried out. Average patient age was 33.8 ± 13.3 years (range 19-67 years), and 57 (58.1%) patients were females. The comparison of patients according to GFR showed that patients with decreased GFR (<60 mL·min-1·(1.73 m2)-1) were older, had lower levels of hematocrit,
hemo-globin and platelets and higher levels of urea and creatinine. Independent risk factors for decreased GFR were advanced age (OR = 21.6, P < 0.0001) and anemia (OR = 39.6, P < 0.0001). Patients with glomerular hyperfiltration tended to be younger, had higher levels of hematocrit, hemoglobin and platelets and lower levels of urea and creatinine, with less frequent urinary abnormalities. Hydroxyurea, at the dosage of 500-1000 mg/day, was being administered to 28.5% of the patients, and there was no significant difference regarding renal function between the two groups. Further studies are required to establish the best therapeutic approach to renal abnormalities in SCD.
Key words: Sickle cell disease; Kidney disease; Glomerular filtration rate; Creatinine; Chronic kidney disease; Hydroxyurea
Introduction
Correspondence: E.F. Daher, Rua Vicente Linhares, 1198, 60135-270 Fortaleza, CE, Brasil. E-mail: ef.daher@uol.com.br or geraldobezerrajr@yahoo.com.br
Received November 17, 2011. Accepted April 24, 2012. Available online May 18, 2012. Published July 2, 2012.
Sickle cell disease (SCD) is the most common he-reditary hematologic disease in the world and is a Public Health problem in tropical countries (1). In Brazil, the prevalence of SCD among Afro-descendants is 0.1-0.3% (2). Renal abnormalities in SCD include microalbuminu-ria, proteinumicroalbuminu-ria, tubular dysfunction, and glomerulopa-thies (1,3). Patients with SCD have abnormalities in renal hemodynamics, and young patients present increased glomerular filtration rate (GFR), which seems to be as-sociated with increased sensitivity to prostaglandins, since treatment with indomethacin significantly reduces GFR among these patients (1). The objective of this study was to investigate renal function abnormalities in SCD patients in Brazil.
Patients and Methods
A retrospective study was conducted on a cohort of 98 patients with SCD followed up at a tertiary hospital in Fortaleza city, Northeast Brazil, using a review of medical records. The study protocol was reviewed and approved by the Ethics Committee of Universidade Federal do Ceará.
Clinical and laboratory characteristics at the time of the most recentmedical examswere analyzed. Renal function was evaluated by the estimation of GFR by the criteria of
the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) (4). We compared patients with normal GFR to
patients with decreased GFR (<60 mL·min-1·(1.73 m2)-1) and
Sickle cell disease and the kidney 653
between patients according to the use of hydroxyurea was also done.
Data were analyzed using the SPSS version 17.0 software pack-age. A comparison of clinical and laboratory parameters according to
GFR was done. P values <0.05 were
considered to be statistically signifi-cant. The Fisher exact test and the χ2
test were used to analyze allele fre-quencies in the different groups. Dif-ferences between two independent variables were evaluated using the
Student t-test or the Mann-Whitney
test, as appropriate.
Results
A total of 98 patients were included. The average age was 33.8 ± 13.3 years (range 19-67 years), and 57 (58.1%) patients were females. The comparison of patients according to GFR showed
that patients with decreased GFR (<60
mL·min-1·(1.73 m2)-1) were older, had
lower levels of hematocrit, hemoglobin and platelets and higher levels of urea and creatinine, as summarized in Table 1. Urinary abnormalities (leukocyturia and proteinuria) were also more fre-quent among patients with decreased GFR. Independent risk factors for de-creased GFR were advanced age (OR
= 21.6, 95%CI = 4.0-134.6, P < 0.0001) and anemia (OR = 39.6, 95%CI = 5.1-417.6, P < 0.0001). A comparison of
GFR according to age showed that patients older than 40
years had GFR <60 mL/min more frequently than younger
patients (13 vs 1.5%, P = 0.03), as shown in Table 2. Patients with glomerular hyperfiltration tended to be younger, had higher levels of hematocrit, hemoglobin and platelets and lower levels of urea and creatinine, with less frequent urinary abnormalities compared to patients with normal and decreased GFR (Table 1). Chronic infection by hepatitis C virus was detected in 6 patients (6.1%), and by hepatitis B virus in 3 (3.0%). None of these patients had decreased GFR (Table 1). Hydroxyurea, at the dosage of 500-1000 mg/day, was being administered to 28 patients (28.5%), with a mean time of treatment from 1 to 2 years, and there was no significant difference regarding renal function between the two groups (Table 3).
Discussion
The present study investigated the occurrence of renal
function abnormalities in a cohort of patients with SCD in Brazil. SCD is associated with important renal abnormalities,
including urine concentration and acidification defects, ab
-normal potassium excretion, proteinuria, and increased GFR (1), all potential risk factors for loss of renal function.
An increase in GFR (glomerular hyperfiltration) was
detected in a high proportion of the patients studied (53%). Previous studies found higher GFR and increased renal
Table 1. Comparison of decreased filtration and hyperfiltration with normal glomerular filtration rate (GFR) in a population of sickle cell disease patients.
Normal GFR (N = 41)
GFR <60 mL/min (N = 5)
GFR >120 mL/min (N = 52)
Age (years) 35 ± 15 49 ± 12* 31 ± 10
Gender
Male 20 (48%) 3 (60%) 18 (34%)
Female 21 (52%) 2 (40%) 34 (66%)
Hematocrit (%) 23 ± 4.9 18 ± 2.6* 26 ± 3.6+ Hemoglobin (g/dL) 8.2 ± 1.6 6.5 ± 1.0* 8.6 ± 1.2+ White blood cells (/mm3) 9912 ± 5229 7975 ± 1814 11697 ± 7921 Platelets (/mm3) 347352 ± 152592 222500 ± 83556 413078 ± 131799+ Fasting glucose (g/dL) 79 ± 11 89 ± 12 82 ± 8.5
Urea (mg/dL) 27 ± 17 87 ± 74* 17 ± 9.8+
Creatinine (mg/dL) 0.8 ± 0.2 2.6 ± 1.2* 0.5 ± 0.1+ K+ (mEq/L) 5.3 ± 0.4 4.3 ± 0.4* 4.6 ± 0.3+ Na+ (mEq/L) 136 ± 2.0 138 ± 5.6 137 ± 2.5+
AST (IU/L) 40 ± 20 66 ± 36* 41 ± 22
ALT (IU/L) 26 ± 20 42 ± 19 29 ± 28
B virus 0 0 3 (5.7%)
C virus 5 (12.1%) 0 1 (1.9%)
Hematuria 1 (2.4%) 0 2 (3.8%)
Leukocyturia 1 (2.4%) 2 (40%)* 1 (1.9%)
Proteinuria 0 2 (40%)* 1 (1.9%)
Data are reported as means ± SD or as number with percent in parentheses. Normal GFR (glomerular filtration rate) = 90-120 mL/min. AST = aspartate aminotransferase; ALT = alanine aminotransferase. *P < 0.05 compared to normal GFR; +P < 0.05 com -pared to normal GFR (Student t-test and Fisher exact test).
Table 2. Comparison of patients with sickle cell disease accord-ing to GFR and age.
≥40 years (N = 31) <40 years (N = 67) GFR <60 mL/min 4 (13%) 1 (1.5%)* GFR >120 mL/min 12 (38.7%) 40 (59.7%) Normal GFR 15 (48.3%) 26 (38.8%)
plasma flow in patients with SCD compared
to controls (5). The use of equations to esti-mate GFR is of crucial importance for an early detection of renal function abnormalities and should be used in every patient with SCD for
an early detection of glomerular hyperfiltration
and to adopt measures to slow the progres-sion of kidney disease, such as the blockade of the renin-angiotensin-aldosterone system using an angiotensin-converting enzyme inhibitor or an angiotensin II receptor an-tagonist (6). Recent studies have shown that the use of angiotensin-converting enzyme inhibitors in patients with SCD and proteinuria reduces urinary protein excretion (7), and this therapy could slow the progression of kidney disease.
Patients with glomerular hyperfiltration
tended to be younger, had higher levels of hematocrit, hemoglobin and platelets and lower levels of urea and creatinine, with less
frequent urinary abnormalities. These find
-ings demonstrate that this is an early marker of renal dysfunction, because it occurs in the
first years of the disease, and in some cases
it can be detected in childhood (1). Hyperfil
-tration can lead to glomerulosclerosis and chronic kidney disease can then develop (8),
possibly explaining the finding that advanced
age was associated with decreased GFR in the present study.
Decreased GFR was associated with
ad-vanced age and anemia, which suggests that loss of renal function occurs with the progression of SCD and can be associated with uncontrolled disease, since these patients more frequently had anemia. Decreased GFR was found in 5.1% of the patients studied, and this prevalence was higher than that estimated for the Brazilian population, which is thought to have a 0.5% prevalence of chronic kidney disease among adults (9). This suggests that SCD patients have a higher risk to develop chronic kidney disease than the general population, so that measures to protect renal function should be adopted in this group of patients. Only 6 patients (6.1%) had hepatitis C virus and 3 (3.0%) had B virus. None of these patients had decreased GFR, so we can say that there is no association of these viruses with loss of renal function in this population. SCD is associated with an increased risk of infection. In a recent cohort of 1415 SCD patients from Salvador, Brazil, C virus infection was found in 13.4%, a higher value than observed in our study, and the prevalence of B virus was similar to that found by us (3.1%) (10).
Hydroxyurea was being used by 28.5% of the patients. The use of hydroxyurea in SCD is still low and there is also poor compliance by some patients (11). Hydroxyurea could
also have a beneficial impact by decreasing the chronic
complications of SCD (1). In the present study, there was no difference in renal function according to the use of hy-droxyurea, perhaps due to the relatively small number of patients taking this medication.
We conclude that SCD is associated with important
renal function abnormalities, mainly regarding GFR. Glomerular hyperfiltration was observed in younger pa-tients, reflecting the initial stages of renal involvement. Decreased GFR was associated with advanced age and anemia. Further studies are required to establish the besttherapeutic approach to renal abnormalities in SCD. Specific treatment with an angiotensin-converting enzyme inhibitor or angiotensin II receptor antagonist should be considered in these patients in order to slow the progression of kidney disease. The role of hydroxyurea in preventing and/or treating renal function abnormalities in SCD remains to be investigated.
Acknowledgments
We are very grateful to the team of physicians, residents,
medical students, and nurses from the Hospital Universitário
Table 3. Comparison of patients with sickle cell disease according to the use of hydroxyurea.
Hydroxyurea treatment (N = 28)
No hydroxyurea treatment (N = 70)
Age (years) 37 ± 10 32 ± 14
Gender
Male 11 (39%) 30 (42%)
Female 17 (61%) 40 (58%)
Hematocrit (%) 24 ± 4.0 24 ± 4.4
Hemoglobin (g/dL) 8.4 ± 1.4 8.4 ± 1.4
White blood cells (/mm3) 9765 ± 4381 11696 ± 8076 Platelets (/mm3) 380718 ± 138366 386780 ± 148253 Fasting glucose (g/dL) 81 ± 11 82 ± 8.5
Urea (mg/dL) 23 ± 27 20 ± 12
Creatinine (mg/dL) 0.7 ± 0.8 0.6 ± 0.5
K+ (mEq/L) 4.7 ± 0.3 4.8 ± 0.6
Na+ (mEq/L) 137 ± 2.2 137 ± 3.2
AST (IU/L) 48 ± 25 40 ± 20
ALT (IU/L) 37 ± 36* 24 ± 17
Hematuria 1 (3.5%) 2 (2.8%)
Leukocyturia 2 (7.1%) 2 (2.8%)
Proteinuria 1 (3.5%) 2 (2.8%)
GFR <60 mL/min 8 (28%) 33 (48%)
GFR >120 mL/min 18 (64%) 34 (48%)
Sickle cell disease and the kidney 655
Walter Cantídio, Universidade Federal do Ceará, for provid
-ing technical support for the development of this research
and for the exceptional assistance provided to the patients.
We acknowledge CNPq for financial support.
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